MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma

Ling Tao; Mahmoud A. Mohammad; Giorgio Milazzo; Myrthala Moreno-Smith; Tajhal D. Patel; Barry Zorman; Andrew Badachhape; Blanca E. Hernandez; Amber B. Wolf; Zihua Zeng; Jennifer H. Foster; Sara Aloisi; Pavel Sumazin; Youli Zu; John Hicks; Ketan B. Ghaghada; Nagireddy Putluri; Giovanni Perini; Cristian Coarfa; Eveline Barbieri

doi:10.1038/s41467-022-31331-2

MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma

Ling Tao, Mahmoud A. Mohammad, Giorgio Milazzo, Myrthala Moreno-Smith, Tajhal D. Patel, Barry Zorman, Andrew Badachhape, Blanca E. Hernandez, Amber B. Wolf, Zihua Zeng, Jennifer H. Foster, Sara Aloisi, Pavel Sumazin, Youli Zu, John Hicks, Ketan B. Ghaghada, Nagireddy Putluri, Giovanni Perini, Cristian Coarfa, Eveline Barbieri

Research output: Contribution to journal › Article › peer-review

37 Scopus citations

Abstract

Neuroblastoma (NB) is a childhood cancer arising from sympatho-adrenal neural crest cells. MYCN amplification is found in half of high-risk NB patients; however, no available therapies directly target MYCN. Using multi-dimensional metabolic profiling in MYCN expression systems and primary patient tumors, we comprehensively characterized the metabolic landscape driven by MYCN in NB. MYCN amplification leads to glycerolipid accumulation by promoting fatty acid (FA) uptake and biosynthesis. We found that cells expressing amplified MYCN depend highly on FA uptake for survival. Mechanistically, MYCN directly upregulates FA transport protein 2 (FATP2), encoded by SLC27A2. Genetic depletion of SLC27A2 impairs NB survival, and pharmacological SLC27A2 inhibition selectively suppresses tumor growth, prolongs animal survival, and exerts synergistic anti-tumor effects when combined with conventional chemotherapies in multiple preclinical NB models. This study identifies FA uptake as a critical metabolic dependency for MYCN-amplified tumors. Inhibiting FA uptake is an effective approach for improving current treatment regimens.

Original language	English (US)
Article number	3728
Pages (from-to)	3728
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-31331-2
State	Published - Jun 28 2022

Keywords

Animals
Cell Line, Tumor
Fatty Acids
N-Myc Proto-Oncogene Protein/genetics
Neuroblastoma/metabolism

ASJC Scopus subject areas

General Physics and Astronomy
General Chemistry
General Biochemistry, Genetics and Molecular Biology

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Tao, L., Mohammad, M. A., Milazzo, G., Moreno-Smith, M., Patel, T. D., Zorman, B., Badachhape, A., Hernandez, B. E., Wolf, A. B., Zeng, Z., Foster, J. H., Aloisi, S., Sumazin, P., Zu, Y., Hicks, J., Ghaghada, K. B., Putluri, N., Perini, G., Coarfa, C., & Barbieri, E. (2022). MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma. Nature Communications, 13(1), 3728. Article 3728. https://doi.org/10.1038/s41467-022-31331-2

Tao, L, Mohammad, MA, Milazzo, G, Moreno-Smith, M, Patel, TD, Zorman, B, Badachhape, A, Hernandez, BE, Wolf, AB, Zeng, Z, Foster, JH, Aloisi, S, Sumazin, P, Zu, Y, Hicks, J, Ghaghada, KB, Putluri, N, Perini, G, Coarfa, C & Barbieri, E 2022, 'MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma', Nature Communications, vol. 13, no. 1, 3728, pp. 3728. https://doi.org/10.1038/s41467-022-31331-2

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abstract = "Neuroblastoma (NB) is a childhood cancer arising from sympatho-adrenal neural crest cells. MYCN amplification is found in half of high-risk NB patients; however, no available therapies directly target MYCN. Using multi-dimensional metabolic profiling in MYCN expression systems and primary patient tumors, we comprehensively characterized the metabolic landscape driven by MYCN in NB. MYCN amplification leads to glycerolipid accumulation by promoting fatty acid (FA) uptake and biosynthesis. We found that cells expressing amplified MYCN depend highly on FA uptake for survival. Mechanistically, MYCN directly upregulates FA transport protein 2 (FATP2), encoded by SLC27A2. Genetic depletion of SLC27A2 impairs NB survival, and pharmacological SLC27A2 inhibition selectively suppresses tumor growth, prolongs animal survival, and exerts synergistic anti-tumor effects when combined with conventional chemotherapies in multiple preclinical NB models. This study identifies FA uptake as a critical metabolic dependency for MYCN-amplified tumors. Inhibiting FA uptake is an effective approach for improving current treatment regimens.",

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AU - Tao, Ling

AU - Mohammad, Mahmoud A.

AU - Milazzo, Giorgio

AU - Moreno-Smith, Myrthala

AU - Patel, Tajhal D.

AU - Zorman, Barry

AU - Badachhape, Andrew

AU - Hernandez, Blanca E.

AU - Wolf, Amber B.

AU - Zeng, Zihua

AU - Foster, Jennifer H.

AU - Aloisi, Sara

AU - Sumazin, Pavel

AU - Zu, Youli

AU - Hicks, John

AU - Ghaghada, Ketan B.

AU - Putluri, Nagireddy

AU - Perini, Giovanni

AU - Coarfa, Cristian

AU - Barbieri, Eveline

PY - 2022/6/28

Y1 - 2022/6/28

N2 - Neuroblastoma (NB) is a childhood cancer arising from sympatho-adrenal neural crest cells. MYCN amplification is found in half of high-risk NB patients; however, no available therapies directly target MYCN. Using multi-dimensional metabolic profiling in MYCN expression systems and primary patient tumors, we comprehensively characterized the metabolic landscape driven by MYCN in NB. MYCN amplification leads to glycerolipid accumulation by promoting fatty acid (FA) uptake and biosynthesis. We found that cells expressing amplified MYCN depend highly on FA uptake for survival. Mechanistically, MYCN directly upregulates FA transport protein 2 (FATP2), encoded by SLC27A2. Genetic depletion of SLC27A2 impairs NB survival, and pharmacological SLC27A2 inhibition selectively suppresses tumor growth, prolongs animal survival, and exerts synergistic anti-tumor effects when combined with conventional chemotherapies in multiple preclinical NB models. This study identifies FA uptake as a critical metabolic dependency for MYCN-amplified tumors. Inhibiting FA uptake is an effective approach for improving current treatment regimens.

AB - Neuroblastoma (NB) is a childhood cancer arising from sympatho-adrenal neural crest cells. MYCN amplification is found in half of high-risk NB patients; however, no available therapies directly target MYCN. Using multi-dimensional metabolic profiling in MYCN expression systems and primary patient tumors, we comprehensively characterized the metabolic landscape driven by MYCN in NB. MYCN amplification leads to glycerolipid accumulation by promoting fatty acid (FA) uptake and biosynthesis. We found that cells expressing amplified MYCN depend highly on FA uptake for survival. Mechanistically, MYCN directly upregulates FA transport protein 2 (FATP2), encoded by SLC27A2. Genetic depletion of SLC27A2 impairs NB survival, and pharmacological SLC27A2 inhibition selectively suppresses tumor growth, prolongs animal survival, and exerts synergistic anti-tumor effects when combined with conventional chemotherapies in multiple preclinical NB models. This study identifies FA uptake as a critical metabolic dependency for MYCN-amplified tumors. Inhibiting FA uptake is an effective approach for improving current treatment regimens.

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KW - Fatty Acids

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MYCN-driven fatty acid uptake is a metabolic vulnerability in neuroblastoma

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